Current Perspectives in Polycystic Ovary Syndrome MARILYN R. RICHARDSON, M.D., University of Kansas Medical Center, Kansas City, Kansas
Polycystic ovary syndrome has been viewed primarily as a gynecologic disorder requiring medical intervention to control irregular bleeding, relieve chronic anovulation, and facil- itate pregnancy. A large body of evidence has demonstrated an association between insulin resistance and polycystic ovary syndrome. The former condition has an estab- lished link with long-term macrovascular diseases such as type 2 diabetes mellitus, hyper- tension, and atherosclerotic heart disease, consequences that also are observed in women with polycystic ovary syndrome. In addition, chronic anovulation predisposes women to endometrial hyperplasia and carcinoma. The purpose of this review is to examine the clinical course of this syndrome, which spans adolescence through menopause, and suggest a simple and cost-effective diagnostic evaluation to screen the large numbers of women who may be affected. Therapy, which should be individualized, should incorporate steroid hormones, antiandrogens, and insulin-sensitizing agents. Weight loss by way of reduced carbohydrate intake and gentle exercise is the most important intervention; this step alone can restore menstrual cyclicity and fertility, and provide long-term prevention against diabetes and heart disease. Treatment alternatives should be directed initially toward the most compelling symptom. Longitudinal care is of paramount importance to provide protection from long-term sequelae. (Am Fam Physi- cian 2003;68:697-704. Copyright© 2003 American Academy of Family Physicians.)
olycystic ovary syndrome (PCOS) are well placed to make early diagnoses of is the most common endocri- PCOS and to help patients avoid the long- nopathy among women of repro- term consequences. ductive age and is estimated to affect up to 10 percent of the U.S. Clinical Course Ppopulation or approximately 5 million Young women of reproductive age most fre- women.1 In 1935, Stein and Leventhal2 quently seek attention initially because of irreg- described masculinized women with amenor- ular menses, hirsutism, or infertility, but PCOS rhea, sterility, and enlarged ovaries containing has a long prodrome with detectable abnor- multiple cysts. The syndrome was placed in malities throughout the life cycle of affected the gynecologic realm for control of chronic women. The earliest manifestations of PCOS anovulation, abnormal menstrual bleeding, are discernible in the peripubertal years. and infertility. Ovarian hyperandrogenism and insulin By the early 1980s, this symptom complex resistance develop with increased frequency in had been linked to hyperinsulinemia and adolescent girls who have premature pub- impaired glucose tolerance.3,4 The connection arche.11,12 In the early reproductive period, to an insulin post-receptor defect was isolated chronic anovulation results in reduced rates of in women with PCOS in the early 1990s.5 As a conception. When pregnancy is achieved, it result of these recent associations, attention is frequently terminates in spontaneous, first- now focused on treating the central deficits trimester loss or is associated with gestational and fundamental problems of hyperandro- diabetes.6 Approximately 25 to 30 percent of genism, hyperinsulinemia, abnormal serum these women show impaired glucose tolerance lipid levels, and obesity that have broader by the age of 30, and 8 percent of women with health implications (Table 1).3,6-10 This new PCOS develop frank type 2 diabetes mellitus information profoundly alters our view of the annually.7 gravity of this condition. Family physicians Markers of premature coronary artery and
AUGUST 15, 2003 / VOLUME 68, NUMBER 4 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 697 tension, and coronary artery disease compared with con- TABLE 1 trol patients. PCOS appears to follow a familial distribu- Intermediate and Long-Term Consequences tion; 40 percent of the sisters and 20 percent of the moth- Associated with PCOS ers of affected women also have the syndrome to varying degrees.15 Infertility Hypertension Recurrent spontaneous abortion Type 2 diabetes mellitus Clinical Features Depression/anxiety Coronary atherosclerosis In many women the symptoms are easily recognizable, Dyslipidemias Cerebrovascular accidents but ethnicity influences the extent of symptoms, especially Total cholesterol (elevated) Endometrial carcinoma with regard to hirsutism and obesity. Therefore, taking a LDL cholesterol (elevated) diligent history with regard to menstrual patterns is cru- HDL2 cholesterol (decreased) Triglycerides (elevated) cial to help establish the diagnosis. The National Institute of Child Health and Development16 held a consensus meeting to develop the following diagnostic criteria for NOTE: These abnormalities may be identified in women with PCOS at various life stages. Listed in order from most common to least PCOS: (1) clinical or biochemical evidence of hyperan- common. drogenism; (2) oligo-ovulation; and (3) exclusion of other PCOS = polycystic ovary syndrome; LDL = low-density lipoprotein; known disorders, such as congenital adrenal hyperplasia HDL = high-density lipoprotein. or hyperprolactinemia. Information from references 3, and 6 through 10. HYPERANDROGENISM The wide spectrum of manifestations ranges from mild acne and increased terminal (coarse) hair growth in midline cerebrovascular disease are prevalent. Women with poly- structures (face, neck, abdomen), to android changes in cystic ovaries are seen to have more extensive coronary body habitus, with waist-to-hip ratios of more than 1. Vari- artery disease by angiography.8 In two case-control stud- ations are influenced by ethnicity,17 as well as coexisting con- ies,9,10 women in their 40s had greater intima-medial thick- ditions (such as hyperthyroidism) that alter androgen ness of the carotid vessels, and more atherogenic lipid pro- biosynthesis. For example, Asian women with PCOS are files: increased total and low-density lipoprotein (LDL) rarely hirsute, but hirsutism is a frequent finding in black cholesterol and triglyceride levels, and decreased high-den- women with PCOS. Yet the actual incidences of hyperan- sity lipoprotein (HDL) cholesterol levels.9,10 drogenemia and insulin resistance do not show a racial These metabolic abnormalities are compounded by the predilection. prevalence of obesity, which occurs in more than 65 per- In addition, nonhirsute women with oligo-ovulation cent of women with PCOS.3 Abnormal androgen produc- may have laboratory evidence of hyperandrogenism. tion declines as menopause approaches (as it does in Frank or rapid “virilization” involving clitoromegaly, vocal women without PCOS), and menstrual patterns somewhat chord thickening, or male-pattern baldness is rare in normalize. However, in retrospective cohort studies,13,14 patients with PCOS and, when present, suggests another perimenopausal and postmenopausal women with a his- cause of hyperandrogenism, such as adrenal disorders or tory of PCOS had increased rates of type 2 diabetes, hyper- androgen-producing tumors (Table 2).18
OLIGO-OVULATION Diagnostic criteria for polycystic ovary syndrome Oligo-ovulation manifests as menstrual irregularity and occurs in 70 percent of women with PCOS. Among include (1) clinical or biochemical evidence of women with more regular menses, many have variable hyperandrogenism, (2) oligo-ovulation, and (3) degrees of ovulatory dysfunction. Often the menstrual for- exclusion of other known disorders, such as mula (i.e., three to five days of menstrual flow every 28 to adrenal hyperplasia or hyperprolactinemia. 35 days) occurs for the first one to two years after menar- che (which occurs at the normal age), but menses then
698 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 68, NUMBER 4 / AUGUST 15, 2003 PCOS
become less frequent, occurring every 45 to 365 days. Because the estrogen from ovarian and adipose tissues Bleeding can be unpredictable, heavy, and pro- stimulates proliferation of endometrium that is not stabi- longed, and chronic endometrial proliferation can lized by post-ovulatory progesterone, bleeding can be result in carcinoma. unpredictable, heavy, and prolonged. Chronic endometrial proliferation can result in carcinoma.
SYMPTOMS WITH VARIABLE FREQUENCY Diagnostic Evaluation Obesity. More than 65 percent of women with PCOS Although there is no consensus as to which laboratory have a body mass index exceeding 27. The fat distribution tests should be used to diagnose PCOS, most physicians often is abdominal/visceral, similar to that frequently asso- agree that the evaluation should screen for hyperandro- ciated with metabolic abnormalities (e.g., hypertension, genemia as well as for abnormalities that have serious dyslipidemia, insulin resistance, glucose intolerance). Most health consequences. Often, the clinical picture is readily women deny childhood obesity and describe normal apparent from the history and physical findings. Thus, test- weight until after menarche. Significant weight gain ing for parameters known to be abnormal in women with appears in the mid-teens and accelerates in the later teens PCOS, such as luteinizing hormone (LH) and follicle- and early 20s. stimulating hormone (FSH) ratios, is unnecessary, redun- The presence of obesity also is influenced by ethnicity. It dant, and expensive. is most common in Hispanic, black, and white women, less In the author’s opinion, the evaluation should follow striking in women of Mediterranean descent, and rare in these principles: exclude other etiologies of amenorrhea, Asian women.17 Obesity is likely to facilitate the metabolic such as prolactin or thyroid abnormalities; exclude other abnormalities of PCOS, as evidenced by the reduction in causes of hyperandrogenism; exclude glucose intolerance; insulin resistance and restoration of cyclic menses follow- and detect insulin resistance and lipid abnormalities. ing weight loss.19 A 1982 study,20 which has been con- firmed by later research, showed that a 10 to 15 percent LABORATORY EVALUATION weight reduction resulted in spontaneous conception in Normal testosterone determinations in the hirsute patient more than 75 percent of obese patients with PCOS. can be misleading, partially because of inherent variation in Acanthosis Nigricans. These velvety, raised skin deposits in intertriginous areas are associated with insulin resis- tance and result from insulin stimulation of the basal lay- TABLE 2 ers of the epidermis. When found in conjunction with Differential Diagnosis of Hyperandrogenism hyperandrogenism, the condition is termed HAIR-AN syndrome (hyperandrogenic-insulin resistant–acanthosis Percentage of 21 nigricans); it occurs in 2 to 5 percent of hirsute women. Most common causes hyperandrogenic women The majority of women with PCOS (70 percent) are insulin resistant, but hyperinsulinemia is far more severe in PCOS 65 to 85 women with HAIR-AN syndrome. HAIR-AN syndrome 1 to 5 Polycystic Ovaries. Ovaries with multiple, small (less than Nonclassic adrenal hyperplasia 1 to 8 10 mm) follicular cysts surrounding the ovarian stroma are Androgen-producing tumors Rare found in 16 to 25 percent of normal women and in female Idiopathic 15 patients with ammenorrhea caused by other etiologies.22 Nearly 80 percent of women with hyperandrogenism have PCOS = polycystic ovary syndrome; HAIR-AN = hyperandrogenic- polycystic ovaries,23 but these may not be present at the time insulin resistant—acanthosis nigricans. of evaluation in women who have used oral contraceptive Adapted with permission from Azziz R. Hirsutism. In: Droege- pills (OCPs), insulin-sensitizing agents, or other forms of mueller W, Sicarra JJ, eds. Gynecology and obstetrics.Vol 5. ovarian suppression. Therefore, the presence of polycystic Philadelphia: Lippincott, 1994:1-22. ovaries on ultrasonography is not a diagnostic essential.
AUGUST 15, 2003 / VOLUME 68, NUMBER 4 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 699 TABLE 3 Laboratory Investigation of PCOS
Test Normal value Purpose